The award is intended to develop the candidate's research skills in, psychophysics, pharmacology, and advanced functional imaging (systems analysis, and fMRI) to equip him for an independent career evaluating mechanisms underlying successful therapy of cognitive dysfunction in neurodegenerative diseases. Once identified, successful medical and/or surgical mechanisms can be manipulated to refine existing, and develop novel therapies. Research Plan: Parkinson's Disease (PD), expected to afflict 1,000,000 Americans by the year 2000, frequently exhibits cognitive deficits (dysexecutive syndrome) in non- demented PD patients, in addition to the 40% with dementia. While the deficits have been linked to frontal cortical dysfunction and/or a disorder of subcortico-frontal connectivity, the functional basis of these deficits in PD remains poorly understood. Dopamine replacement therapy, successful for the motoric signs of PD, falls to improve the dysexecutive syndrome. Pathological studies show 20% loss of cholinergic cells in subcortical nuclei of non-demented PD patients, abnormal cortical choline acetyltransferase, reduced cortical and subcortical nicotinic receptors, and a correlation between cortical nicotinic loss and cognitive dysfunction. Preliminary clinical reports suggest cognitive improvement with non-specific cholinergic therapy. In Specific Aim 1, the candidate proposes a PET study of PD patients performing kinematically-controlled motor learning and execution tasks at baseline and with cholinergic pharmacotherapy. The pharmacological technique will allow him to identify the contribution of receptor families (muscarinic and/or nicotinic) to cholinergic modulation of specific brain networks known to be associated with learning performance. Based on these results, the candidate will test the hypothesis that nicotinic therapy will improve defined aspects of cognitive dysfunction in PD. The candidate wishes to bridge the gap between clinical description of cognitive abnormality, and pathological observation of cholinergic loss, firstly, by quantifying the modulation of cholinergic receptor families on brain networks subserving cognition, then by testing if predicted improvements occur with therapy of a particular receptor family. In Specific Aim 2, the candidate will expand upon a preliminary observation that deep brain stimulation (DBS) may improve learning performance in PD. He will perform a PET study on PD patients on and off subthalamic nucleus (STN) DBS to determine the effect of therapeutic stimulation on the same tasks as in Specific Aim l. This will test the hypothesis that STN DBS may enhance cognitive performance in PD by modulating the expression of subcortico-frontal projection systems associated with motor learning. Educational aims: The candidate has chosen consultants who are expert in each of psychophysics, pharmacology, systems analysis, and fMRI, and plans to attend didactic courses in these fields and present data generated from this study at scientific meetings. Under the general mentorship of Dr. Eidelberg the candidate will be able to smoothly integrate clinical and research activities to allow him to make the transition from trainee to independent physician-scientist.